alpha-halomethyl-(1-oxazole-carbonylindol-3-yl) acetic acids and certain intermediates therefor



United States Patent 3,326,930 a-HALOMETHYL-(1-OXAZOLE-CARBONYLINDOL-S-YL) ACETIC ACIDS AND CERTAIN INTER- MEDIATES THEREFOR Tsung-Ying Shen,Westfield, and Lewis H. Sarett, Princeton, NJ., assignors to Merck &Co., Inc., Rahway, N.J., a corporation of New Jersey N0 Drawing. FiledApr. 29, 1965, Ser. No. 452,022 14 Claims. (Cl. 260307) This applicationis a continuation-in-part of our copending application, Ser. No.222,222, filed Sept. 7, 1962, and now US. Patent No. 3,242,192, issuedMar. 22, 1966.

This invention relates to new chemical compounds. More particularly, itrelates to a new class of compounds of the indole family. Still moreparticularly, it is concerned with new (it-halogenated methyl3-indolylacetic acids having an oxazole, isoxazole or oxadiazolecarboxylic acyl attached to the, nitrogen atom of the indole ring. It isconcerned further with salts, esters and amide derivatives of suchcompounds. In addition, it is concerned with novel intermediates forpreparing the foregoing a-halogenated methyl indolyl acetic acidcompounds. It relates also to the synthesis of such substances.

The new heteroaroyl indolylacetic acid compounds of this invention havethe general structural formula:

I s CHCOR wherein R is selected from the group consisting of oxazole,isoxazole, oxadiazole and substituted oxazole isoxazole and oxadiazolein which the substituents may be halogen, lower alkyl, lower alkoxy,phenyl, benzyl, trifluoromethyl, cyano, thiocarbamoyl, hydroxy loweralkyl, hydroxyphenyl or alkylphenyl;

R is selected from the group consisting of a hydrogen atom and loweralkyl, lower alkenyl, aryl, aralkyl, alkaryl, substituted alkyl andsubstituted aryl radicals;

R is a halogenated methyl radical;

R is selected from the group consisting of hydroxy, NH substituted --NHamine salts, lower a-lkoxy, aralkoxy and OM radicals, said M being acation; and

R is selected from the group consting of hydrogen and halogen atoms, andlower alkyl, lower alkoxy, haloalkyl, nitro, amino, substituted amino,cyano, aminomethyl, alkyl-substituted aminomethyl, mercapto,dialkylsulfonamide and benzylmercapto radicals.

A critical feature of the above compounds is the presence of aheteroaroyl radical attached to the N-l position of the indole nucleus.These acyl groups may be further substituted in the aromatic ringsthereof with hydrocarbon groups or with functional substituents. Theterm functional substituent, as used herein, is meant one other thanhydrogen or hydrocarbon.

The aromatic rings (Ar) of such groups may contain, and in the preferredcompounds do contain, at least one functional substiuent. Thissnbstituent may be a hydroxy or an etherified hydroxy (hydroxycarbonoxy)group such as a lower alkoxy, aryloxy or an aralkoxy radical, e.g.,methoxy, ethoxy, isopropoxy, propoxy, allyloxy, phenoxy, benzyloxy,halobenzyloxy, lower alkoxybenzyloxy and the like. Said functionsubstituent may also be a nitro group, a halogen, an amino group or asubstituted amino group, representative examples of which that might bementioned are acylamino, amineoxide, ketimines, urethanes,

lower alkylamino, lower dialkylamino, amidine, acylated amidines,hydrazine or a substituted hydrazine, alkoxyamines and sulfonatedamines. Furthermore, said functional substiuent may be a mercapto or asubstituted mercapto radical of the type exemplified by alkylthio groupssuch as methylthio, ethylthio, and propylthio and arylthio oraralkylthio groups, e.g., benzylthio and phenyl thio. The N-1 aroylradical may, if desired, be haloalkylated, as with trifluorornethyl,trifiuoroethyl, perfluoroethyl, S-chloroethyl or like substituent,acylated as with acetyl, propionyl, benzoyl, phenylacetyl,trifiuoroacetyl and like acyl groups, or it may contain a haloa-lkoxy orhaloalkylthio substituent. In addition, the invention embraces compoundswherein the aroyl radical contains a sulfamyl, benzylthiomethyl, cyano,sulfonamido or dialkylsulfonamido radical. Further, it may contain acarboxy substituent, or a derivative thereof, such as an alkali metalsalt or a lower alkyl ester of the carboxy radical, an aldehyde, azide,amide, hydrazide and the like, or an aldehyde derivative of the typerepresented by acet-als or thioacetals. In the preferred compounds, theN-l aroyl radical is benzoyl and the functional substituent is in thepara position of the six-membered ring.

In accordance with this invention, the N-l group may be oxazole,isoxazole or oxadiazole carboxylic acyl derivatives, with or withoutsubstituents.

R situated in the 2-position of the indole ring nucleus, may behydrogen, although it is preferred that there be present at thisposition of the molecule a hydrocarbon radical having less than ninecarbon atoms. Lower alkyl groups such as methyl, ethyl, propyl or butylare the most satisfactory although aryl, alkaryl and aralkyl groups arealso advantageous, such as phenyl, benzyl and tolyl.

Furthermore, the alkoxy, halo, amino, substituted amino and nitrosubstituted derivatives of the foregoing are within the purview of thisinvention as are indoles having at the 2-position an unsaturatedaliphatic radical such as allyl or vinyl or a cyclic aliphatic residueof the type cyclohexyl.

A further critical feature of the foregoing compounds is that they are3-indolylacetic acids in which the acetic acid iii-carbon atom isfurther substituted by a halogenated methyl group (R including themono-, di -and tri-halo substituted methyls, such as, for example,trifiuorometh yl, difiuoromethyl, dibromomethyl, fluorochloromethyl,chloromethyl, fiuoromethyl, and the like.

In the preferred compounds of the invention, R is lower alkyl, loweralkoxy, nitro, amino or substituted amino group. Examples of the alkyland alkoxys that are embraced herein are methyl, ethyl, propyl, t-butyl,methoxy, ethoxy, isopropoxy and the like radicals. Examples of thesubstituted aminos are those derived from alkyl amines such as methylamine, ethyl amine, isopropyl amine, butyl amine, diethyl amine,ethyl-sec-butyl amine, diisopropyl amine and the like, alkanolaminessuch as ethanolamine, diethanolamine, Z-amino-l-butanol, morpholine andthe like, aryl amines such as aniline, diphenylamine and the like, mixedaromatic-aliphatic amines such as monomethylaniline, monoethylanilineand the like, aralkyl amines such as benzylamine, [3-phenylethylamineand the like, halo-substituted aliphatic or aromatic amines such as,B-chlor-oethylamine, para-chloroaniline, para-chlorobenzyl amine andthe like, and other substituted aliphatic or aromatic amines such asfi-methoxyethyl amine, para-methoxy aniline, para-tolyl amine and thelike. R is not limited to the foregoing classes of substituents,however, and may, if desired, represent substituents such as hydrogen,aryl, aryloxy, hydroxy, mercapto, halo, haloalkyl such as -CF CHF andthe like, nitro, haloalkyl, cyano, sulfarnyl, sulfoxide, amino- Z5methyl, substituted aminomethyl, carboxy and carboalkoxy groups.

In addition to the a-(3-indolyl)acetic acids described herein, theesters, salts and amide derivatives thereof represent an additionalaspect of the invention. The esters are important intermediates in thesynthesis of the free acids, and in many cases are themselves ofimportance as end products. Among the preferred esters are the loweralkyl esters such as the methyl, ethyl, propyl or t-butyl esters, andthe aralkyl esters such as the benzyl, p-halobenzyl, and like estershaving less than nine carbon atoms. The salts of these neww(heteroaroyl-3-indolyl)-acetic acids can be obtained by treatment ofthe free acid with base under mild conditions. In this manner there maybe obtained salts of alkali metals such as lithium, sodium andpotassium, the aluminum or magnesium salts, or salts of alkaline earthmetals such as barium and calcium. Salts of organic amines such asalkylamine, morpholine, choline, methyl cyclohexylamine or glucosaminemay be obtained by reacting the acid with the appropriate organic base.Salts of heavy metals such as zinc and iron are also within the purviewof this invention.

The following compounds are representative of those contemplated by thisinvention and which may be prepared by the procedures discussedherein-below:

methyl a-trifluoromethyl-a-[1-(Z-benzyl-S-chloroxazole- 2-carbonyl)-2methyl-S-methoxy-3 -indolyl] -acetate,

u-difluoromethyl-a-[ 1- (oxazole-Z-carbonyl) -2,5-

dimethyl-3-indolyl]-acetic acid,

methyl a-trifluoromethyl-al-(2-methyl-5-trifiuoromethyloXazole-4-carbonyl) -2-methyl-5-methoxy- 3-indolyl]-acetate,

a-trifluoromethyl-a- 1- (4-methyloxazole-5-carbonyl2-methyl-5-methoXy-3-indolyl] -acetamide,

ethyl oc-diflllOI'OChlOPOIl'lCthYl-ocl- (Z-benzyloxazole- 4-carbonyl)-2-methyl-5-rnethoxy-3-indolyl] -acetate,

benzyl a-fiuoromethyl-a-[ 1-( oxazole-4-carbonyl) -2-ethyl-5-methyl-3-indolyl] -acetate,

propyl a-trifluoromethyl-a-[1-(5-methyl-1,2,3-oxadiazole- 4-carbonyl-2methyl-5-methoXy-3-ind-olyl] -acetate,

ot-trifluoromethyl-w[1-(3-p-chlorophenyl-5-methylisoXazle-4-carbonyl)-2-methyl-5 -metl1oXy-3- indolyl] -acetic acid,

a-trifiuoromethyl-u-[ 1- Z-phenyl--methoXyoXazole-4- carbonyl-2-methyl-5-rnethoxy-3-indolyl] acetamide,

methyl a-bromomethyl-a-[1-(oxazole-2-carbonyl)-2-methyl-5-methoxy-3-indolyl -acetate,

u-trifiuOromethyl-a-E 1- Z-benzyl-4-cyanoX-aZole-5- carbonyl-2methyl-5-methoxy-3 -indolyl] acetic acid and the like.

The a-halomethyl-l-aroyl-(or l-heteroaroyl)-3-indoly1 acetic acidcompounds of this invention and their corresponding esters and amideshave a high degree of antiinfiammatory activity and are effective in theprevention and inhibition of granuloma tissue formation. Certain of thempossess this activity in high degree and are of value in the treatmentof arthritic and dermatological disorders and in like conditions whichare responsive to treatment with anti-inflammatory agents. In addition,the compounds of this invention have a useful degree of antipyreticactivity. For these purposes, they are normally administered orally intablets or capsules, the optimum dosage depending, of course, on theparticular compound being used and the type and severity of infectionbeing treated. Although the optimum quantities of these compounds ofthis invention to be used in such manner will depend on the compoundemployed and the particular type of disease condition treated, oral doselevels of preferred compounds in the range of 1.0-2000 mg. per day areuseful in control of arthritic conditions, depending on the activity ofthe specific compound and the reaction sensitivity of the patient.

The novel tat-halogenated methyl S-indolylacetic acids of this inventionare prepared from 3-a-haloacetyl indoles that have been acylated in theN-l position of the indole nucleus with an oxazole, isoxazole oroxadiazole carboxylic acyl radical. These useful synthetic intermediatesare also novel compounds and an additional feature of this invention andmay be chemically represented as follows:

wherein X, Y and Z are selected from the class consisting of hydrogen,and halogen atoms, at least one of which is a halogen, preferablychlorine, bromine or fluorine, and R R and R are as previously defined.They are preferably prepared by reacting an indole that is unsubstitutedin the N-l and C-3 positions, but having the desired R and Rembellishments, with a member selected from the group consisting ofhalogenated acetic acid anhydride and halogenated acetyl halide to formthe corresponding 3-haloacety1 indole which is then treated with anacylating agent capable of introducing the desired aromatic carboxylicacyl moiety in the N-l position of the indole nucleus. Alternatively,the foregoing two steps may be reversed, that is, the starting indolemay first be acylated in the N-l position with the appropriate aroyl orheteroaroyl moiety followed by the introduction of the u-haloacetylmoiety in the C-3 position.

In either instance, the reaction of the indole with the respectivehalogenated acetic acid anhydride or halogenated acetyl halide iscarried out by heating the reagents together at temperatures above 50 C.and preferably in the range of from -250 C. Preferably, the reaction isrun at the reflux temperature of the particular halogenated acetic acidanhydride or halogenated acetyl halide employed. In the case of thelower boiling acetic anhydrides or acetyl halides, a closed reactionvessel will be advantageous.

The acylation reaction is preferably conducted by intimately contactingthe N-l unsubstituted indole with an oxazole, isoxazole or oxadiazolecarboxylic acid halide in the presence of a strongly basic condensingagent, such as sodium hydride, potassium hydride, sodamide, an alkyllithium or an alkali metal alkoxide, in a suitable solvent medium. Themetallo derivative of the indole reactant forms first and this, in turn,reacts with the heteroaroyl halide to form the corresponding N-lacyl-ated indole.

An alternative method of acylating the 1-position is by use of anactivated aryl ester of the acylating acid, such as the p-nitrophenylester. This latter is prepared by mixing the acid and p-nitrophenol intetrahydrofuran and adding dicyclohexyl carbodiimide in tetrahydrofuranslowly. The dicyclohexylurea which forms is removed by filtration andthe p-nitrophenyl ester is recovered from the filtrate. Alternatively,there can also be used the anhydride, azide or thiophenolic ester of theacylating acid. Whichever is used, the acylation of the a-(3-indolyl)-lower aliphatic acid starting material is achieved by forming a sodiumsalt of said material with sodium hydride in an anhydrous solvent andadding the acylating agent.

In the acylation step, the reaction medium is not unduly critical and itis preferred to employ anhydrous organic solvents such as, for example,the alkylformamides, such as dimethylformamide, diethylformamide and thelike, aromatic hydrocarbons such as benzene, toluene and Xylene,mixtures of said dialkylformarnides and said aromatic hydrocarbons,ethers such as diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran anddiphenyl ether and nitrobenzene. The temperature of the reaction is notcritical although it is preferred to carry out the acylation attemperatures ranging from O30 C. Lower tempera- 5 tures may be employedif the particular reactants are unduly susceptible to decomposition.

In a preferred embodiment of this invention, the process of synthesizingthe subject a-halomethyl 3-indolylacetic acids comprises condensing a3-a-haloacetyl indole that is acylated in the N-l position of the indolenucleus with an oxazole, isoxazole or oxadiazole carboxylic acyl radicalof less than three fused rings with an a-halo ester to form a glycidicester, converting said glycidic ester to its corresponding acid,decarboxylating said acid to an aldehyde treating said aldehyde withhydroxylamine to formthe corresponding oxime, dehydrating said oxime toform the corresponding nitrile, treating said nitrile with alkanol andhydrogen halide to form an imino-alkyl ester hydrohalide which, uponhydrolysis, forms the corresponding alkyl ester, and hydrolyzing saidalkyl ester under mild conditions.

Accordingly, the tit-halogenated methyl-B-indolyl-acetic acids of thisinvention may be prepared by reacting a halogenated acetic acidanhydride with indole itself or an indole that has been presubstitutedin the 2- and/ or 5-positions with the desired embellishments, therebyintroducing an a-haloacetyl group in the 3-position of the indolenucleus:

CXYZ

' B (OXYZ-COMO R3 R2 N N H H wherein R and R are substituents aspreviously described and X, Y and Z are selected from the groupconsisting of hydrogen and halogen atoms, at least one being a halogen.The resulting 3-a-haloacetyl indole is then acylated in the N-l positionby treatment with an acylating agent such as a heteroaroyl halide:

(IJXYZ CXYZ R C=O aroyl or hetero- R =0 aroyl halide NaH, DMF, 0-10 C.R, N N H I wherein R is an aroyl or heteroaroyl group as previouslydescribed. Alternatively, the foregoing two steps may be reversed, thatis, the starting indole could first be acylated in the N-1 position withthe heteroaroyl moiety, followed by the introduction of the a-haloacetylmoiety in the 3- position. In either event, the resulting product isthen condensed with an a-halo ester such as chloroacetic acid ester inthe presence of a basic condensing agent such as sodium ethoxide, sodiumamide or sodiumhydride to form the corresponding a,18-epoxy ester(glycidic ester):

wherein R is an alkyl or aralkyl radical. The glycidic estercondensation reaction is carried out under anhydrous conditions, with orwithout a solvent medium, and preferably in an inert atmosphere. Thereaction is preferably run at 0 C. or below, temperatures as low as 1 Adiscussion on the formation of glycidic esters and their conversion toaldehydes will be found in Organic Reactions, vol. V, Adams et aL,Chapter (1949), published by John Wiley & Sons, Inc. (New York).

8'0 C. being advantageous. After reaction periods ranging from a fewhours to a few days, the reaction mixture is treated with dilute acidand-the organic product extracted in the usual way by suitable organicsolvents or separated by vacuum distillation. The resulting glycidicester is then converted to the corresponding acid by mild alkalinehydrolysis, followed by decarboxylation to yield an aldehyde degraded byone carbon atom:

CXYZ

Alternatively, when R above is a tertiary alkyl radical, the glycidicester is preferably converted to the degraded aldehyde by heating to thedecomposition point, as, for example, by direct pyrolysis at -200 C.,under nitrogen and in the presence of powdered copper:

The foregoing aldehydes may be converted to an oxime by the usualtreatment with hydroxylamine, such as, for example, by treatment withhydroxylamine acetate in aqueous ethanol to which a base is added withwarming:

CXYZ

The resulting oxime is dehydrated to a nitrile as, for example, bytreatment with a mild dehydrating agent such as acetic anhydride, or,prefer-ably, by treatment with ehloroforruate R1 The resulting nitrilemay be partially hydrolyzed, under mild alkaline or acidic conditions,to form the corresponding amides of this invention which, upon furtherhydrolysis, yields the corresponding acids themselves. Preferably, theresulting nitrile is converted to an alkyl ester by means of anintermediate imino-alkyl ester hydrohalide synthesis followed byhydrolysis. For example, the nitriles are treated in an alkanol (ROH)solution with a hydrogen halide, such as hydrogen chloride and hydrogenbromide, in the strict absence of water to form the correspondingimino-alkyl ester hydrohalide. The addition of Water to the reactionmixture leads to hydrolysis of the imino-ester with formation of thecorresponding Said esters, which are embraced within the purview of thisinvention, are then hydrolyzed under mildly alkaline or mildly acidicconditions to yield the corresponding whalomethyl-3-indolylacetic acidsof this invention:

CXYZ CXYZ However, since the l-acyl group of the above alkyl esterproduct may also undergo some hydrolysis, said acids are usuallyobtained in admixture with the corresponding N-l unsubstituted(deacylated) a-halomethyl-3-indolyl-acetic acid and the aroyl orheteroaroyl moiety in its acid form. The novel acids of this inventionare separated and recovered from such mixtures by conventionaltechniques such as fractional crystallization or by means ofchromatography using a silica gel column and mixtures of ether petroleumether as \the eluent.

The tat-halogenated methyl S-indolylacetic acid amides of thisinvention, acylated in the N-1 position with an oxazole, isoxazole oroxadiazole carboxylic acyl radical of less than three fused rings, maybe prepared from the corresponding a-halogenated methyl 3-indolylaceticacids according to conventional techniques for the preparation of amidesand N-substituted amides. For example, the respective acid may beconverted to a symmetrical anhydride in the presence of a milddehydrating agent such as dicyclohexyl carbodiimide and then treatedwith ammonia to yield the corresponding amide, or with a primary orsecondary amine having the desired substituents in an inert solvent toyield the corresponding substituted amides. Alternatively, therespective acid may be converted to a mixed anhydride by treatment witha nonhydroxylic base such as, for example, a tertiary alkyl amine,pyridine and the like, to yield an acid salt, followed by treatment withan acid halide such as, for example, an alkyl or aryl chloroformate,phosphorous, oxychloride, thionyl chloride and the like, to yield themixed anhydride which may then be treated with ammonia, primary aminesor secondary amines to yield the corresponding amides. In addition, thea-halomethyl-3-indolylacetic acid amides of this invention may beprepared by the mild acid hydrolysis of the correspondinga-halomethyl-3-indolyl acetonitriles.

Among the primary and secondary amines that are operable herein are thealkyl amines such as methyl amine, ethyl amine, isopropyl amine, butylamine, diethylamine, ethyl-sec-butylamine, diisopropyl amine and thelike, a'lkanolamines such as ethanolamine, diethanolamine, 2-amino-l-butanol, morpholine and the like, aryl amines such as aniline,diphenylamine and the like, mixed aromatic-aliphatic amines such asmonomethylaniline, monoethylaniline and the like, aralkyl amines such asbenzylamine, ,B-phenylethylamine and the like, halo-substitutedaliphatic or aromatic amines such as B-chloroethyl amine,para-chloroaniline, parachlorobenzyl amine and the like, and othersubstituted aliphatic or aromatic amines such as fi-methoxyethyl amine,para-tolyl amine, para-methoxy aniline, and the like.

The a-halogenated methyl 3-indolylacetic acids may also be used toprepare the corresponding esters of this invention. For example therespective acid may first be converted to symmetrical or mixedanhydrides as previously described and then reacted with a desired alkylor aralkyl alcohol in the presence of a non-hydroxylic base such as, forexample, a tertiary alkyl amine, pyridine and the like, to yield thecorresponding alkyl or aryl ester.

The synthesis of various compounds of this invention having on theindole ring system a S-substituent which has a nitrogen attached to thehomocyclic ring of the indole is generally based on the S-nitro compoundwhich may subsequently be transformed into the desired 5-substituent.Such transformation can be carried out in a number of ways. Reduction ofthe S-nitro groups gives a S-amino group. Reaction of the amino withalkyl halides gives mono and dialkyl amino groups. If the alkyl halideis a dihaloalkylene group (e.g., 1,4-dibromobutane) a heterocyclic ring(e.g., pyrrolidino) is formed. Similarly, bis(B-chlorethyl)ether willgive an N-morpholine compound. Alkylation can also be carried outsimultaneous with reduction, as e.g., with formaldehyde and Raney nickeland hydrogen. Acylation can similarly be carried out on the S-aminocompounds or on the S-nitro (with simultaneous reduction) to giveS-acylarnido Preparation of 2-methyl-3-trifluoroacetyl-5-methoxyindole Amixture of 20 g. of 2-methyl-5-methoxyindo1e and 195 g. oftrifluoroacetic anhydride is heated at 100 C. for 6 hours in aglass-lined bomb with occasional shaking. The reaction mixture is thencooled and filtered, yielding 15 grams of crude product.Recrystallization from ether yields2-methy1-3-trifluoroacetyl-5-methoxyindole (M.P.: 185-185.5 C.).

Analysis.For C H NO F Calculated: C=56.03%; H=3.91%; N=5.44%. Found:C=56.15%; H=4.18%; N=5.23%.

EXAMPLE 2 The procedure of Example 1 is followed using as reactants, inlieu of the trifluoroacetic anhydride and Z-methyl-5-methoxyindole usedtherein, the equivalent quantities of the appropriate halo-substitutedacetic anhydrides and indoles appropriately substituted in the C-2 andC-5 positions of the indole nucleus so as to yield the followingrespective products:

3-trifiuoroacetylindole, 3-trichloroacetyl-2,S-dimethylindole,3-difluoroacetyl-2,S-dimethylindole,2-methyl-3-difluorochloroacetyl-S-methoxyindole,2-ethyl-3-fluoroacetyl-S-methylindole,2-phenyl-3-dichloroacetyl-S-methoxyindole,2-p-tolyl-3-trichloroacetyl-S-methoxyindole,2-methyl-3-dich1oroacetyl-S-nitroindole,2-ethyl-3-trifluoroacetyl-5-methylindole,2-methyl-3-chloroacetyl-5-cyanoindole, 2-butyl-3-trifluoroacetyl-S-benzyloxyindole,2-allyl-3-trifluoroacety1-5methoxyindole,2-methyl-3-difluoroacetyl-S-methylthioindole, 2-methyl-3-trifluoroacetyl-5-dimethylaminoindole,2-1nethyl-3-dibromoacetyl-5-allyloxyindole,2-methyl-3-trifiuoroacetyl-5-benzylmercaptoindole,2-vinyl-3-trifiuoroacetyl-S-methoxyindole,2-p-rnethoxyphenyl-3-dichloroacetyl-5-methoxyindo1e,

and 2-p-chlorophenyl-3-bromochloroacetyl-S-methoxyindole.

The 2- and/or 5-substituted indoles used as starting materials above maybe prepared by a Fischer indole synthesis using the correspondingpara-substituted phenylhydrazine (the para-substituent becoming the5-substituent of the indole) and a reagent having the formula CH COR (inwhich R becomes the 2-substituent of the indole), or by following theprocedures set forth in US. Patent No. 2,825,734.

EXAMPLE 3 Preparation of I-p-(xaz0le-4-carb0nyl)-2-methyl-3-lrifluoroacetyl--meth0xyina'0le To a solution of 3.23 g. (0.013 mole) of2-methyl-3- trifluoroacetyl-S-methoxyindole in 40 cc. of freshlydistilled dimethylformamide (DMF) at 0 C. are added 1.3 g. (0.026 mole)of a sodium hydride-mineral oil suspension (51% NaH) under nitrogen. 3.5grams (0.020 mole) of oxazole-4-carboxylic acid chloride in cc. of DMFare then added and the mixture stirred for 3 hours at 0 C. Excess etheris then added and the reaction mixture stirred at 0 C. for 50 minutes.The mixture is then filtered, the precipitate washed with ether, and theether solution washed twice with water, dried over sodium sulfate, andconcentrated in vacuo. Chromatography on 200 g. of silica gel with 5%(v./v.) ether in petroleum ether as the eluent yields 1.2 g. of a yellowoil which solidified on cooling in Dry Ice. Recrystallization from 5%(v./v.) ether in petroleum ether (cooled in Dry Ice) yields 0.57 g. ofl(oxazole-4-carbonyl)-2-methyl-3-trifiuoroacetyl-S-methoxyindole.

EXAMPLE 4 J (oxazole-4-carb0nyl) -2-m ethyl-3-triflu0r0acety[-5-methoxyindole A. p-Nitrophenyl oxazole-4-carboxylata-In a 500 ml. roundbottom flask (all equipment flame dried) is added 139 g. ofp-nitrophenol and 5.3 g. oxazole-4-carb0xylic acid in 250 ml. drytetrahydrofuran. Through a dropping funnel is added over 30 minutes 20.6g. of dicyclohexylcarbodiimide in ml. of dry tetrahydrofuran. Thereaction is allowed to run overnight with stirring. The dicyclohexylureawhich forms during the reaction is filtered. The filter cake is washedwith dry tetrahydrofuran. The solution is evaporated to dryness. Thesolid is taken up in benzene and washed with sodium bicarbonate solutionand then with water and dried over anhydrous sodium sulfate. Thesolution is concentrated under vacuum to dryness. The solidp-nitrophenyl-oxazole-4-carboxylate is then recrystallized from benzene.

B. 1-(oxaz0le-4-carbonyl) -2-methyl-3-triflu0r0acetyl-5-meth0xyind0le.In a 250 ml. round bottom flask (flame dried equipment) isplaced at 0 C. with nitrogen, 100 ml. of dry dimethylformamide with 10.5g. of 2-methyl-3-trifiuoroacetyl-S-methoxyindole. To this is added 2.5g. of 50% sodium hydride mineral oil mixture. After the mixture isstirred for 30 minutes there is added over 15 minutes a solution of 6.7g. of p-nitrophenyl-oxazole-4-carboxylate in 50 ml. drydimethylformamide. The reaction mixture is stirred for 4 hours at 0 C.under nitrogen followed by stirring under nitrogen at room temperatureovernight. The reaction mixture is then poured into an icewater-ethersolution containing a few ml. of acetic acid and the layers areseparated. The aqueous phase is washed with ether and the ether extractsare combined and dried over sodium sulfate. To the ether solution isadded a saturated solution of hydrogen chloride gas in dry ether. Theether is decanted off, leaving a heavy oil. The oil is washed with etherfollowed by an addition of aqueous sodium bicarbonate solution. Theproduct is then extracted with ether. The ether layer is dried overanhydrous sodium sulfate and concentrated to dryness. The product, 1(oxazole 4 carbonyl) 2 methyl 3 .trifluoro- 'acetyl-i-methoxyindole iscrystallized from benzene- Skellysolve B.

EXAMPLE 5 The procedure of Example 4 is followed, but using asreactants, in lieu of the 2-methyl-3-trifluoroacetyl-5- methoxyindoleand oxazole-4-carboxylic chloride or the p-nitrophenyl-4-oxazolecarboxylate used therein the equivalent quantities of the 3-haloacetylindoles appropriately substituted in the C-2 and C-5 positions of theindole nucleus and the appropriate aroyl and heteroaroyl chlorides so asto yield the following respective products:

1-(2-benzyl-4-cyan-o oxazole-S-carbonyl)-2-ethyl-3-trifluoroacetyl-S-methylindole,

1- 2-benzyl-4-thiocarbamoyloxazole-S-carbonyl) -2-methyl-3-chloroacetyl-5-cyanoindole,

1- 2-phenyl-4-methyloxazole-5-carbonyl) -2-butyl-3-trifluoroacetyl-5-benzyloxyindole,

1-(Z-phenyl-1-methyloxazole-5-carbonyl) -2-allyl-3-trifluoroacetyl-5-methoxyindole,

1- 2-phenyl5-hydroxymethyloxazole-4-carbonyl) -2-methyl-3-difluoroacetyl-5-methy1thioindo-le,

1- (4-methyloxazole-5-carbonyl) -2-methyl-3-trifluoroacetyl-S-dimethylaminoindole,

1-(2-phenyl-4-methyloxazole-5-carbonyl) -2-methyl-3-dibromoacetyl-5-ally1oxyindole,

1- 2-benzyloxazole-4-carbonyl)-2-methyl-3-trifluoroacetyl-S-benzylmercaptoindole,

1-[2-methyl-5-(2,4-dihydroxy-m-tolyl)oxazole-4- carbonyl]-2-vinyl-3-trifiuoroacetyl-5 -methoxyindole,

1- (Z-methyloxazolic-4-carbonyl) -2-n-methoxyphenyl-3-dichloroacetyl-5-methoxyindole,

1- (oxazole-Z-carbonyl) -benzoyl2-p-chlorophenyl-3-bromochloroacetyl-S-methoxyindole, and

1 oxaZole-2-carbonyl) -2-methyl-3 -trifluoroacetyl- 5 -methoxyindole.

EXAMPLE 6 Preparation of tertiary-butyl-B-[I-(oxazo le-4-carbonyl)-Z-methyl-5-methoxy-3-indolyl]-fi-trifluor0methyl glycidate To a solutionof 0.03 mole of 1-(oxaZole-4-carbonyl)-2-methyl-3-trifluoroacetyl-S-methoxyindole and 0.045 mole of t-butylchloroacetate in 250 ml. of dimethoxyethane are added, in portions, 5.2g. of potassium t-butoxide at C. with stirring and under nitrogen. Thereaction mixture is stirred at room temperature for 18 hours and pouredinto 1 liter of iced water containing 3 ml. of acetic acid. The productis extracted with ether, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue is chromatographed on silica gelusing mixtures of ether-petroleum ether in the range of 50-100% ether(v./v.) as the eluent to give the corresponding tertiarybuty1-fl-[l-(oxazole-4-carbonyl) -2-methyl-5 methoxy-3- indolyl]-,8-trifiuoromethyl glycidate.

EXAMPLE 7 Preparation of a-[1-(0xazole-4-carb0nyl)-2 methylmethoxy-3-indo-lyl] -a-trifluoromethyl acetaldoxime A mixture of 3.5 g.of tertiary-butyl-B-[1-(oxaZole-4-carbonyl)-2-methyl-5-methoxy-3-indolyl] ,8 trifiuoromethyl glycidate andabout 500 mg. of copper powder is heated in an oil bath at 150-200 C. at0.1 mm. Hg with stirring. As soon as the pyrolysis slows down, thereaction mixture is cooled in ice and the resulting a-[l-(oxazole 4carbonyl)-2-methyl-5-methoxy-3-indolyl]-a-trifluoromethyl acetaldehydeextracted with ether. The ethereal solution is concentrated in vacuo,dissolved in 50 ml. ethanol and treated with 2 g. of hydroxylamineacetate. The mixture is poured into water and extracted with ether. Theethereal solution is washed with dilute hydrochloric acid, aqueoussodium bicarbonate, water and dried. Evaporation of the solution gives asyrup which is chromatographed on 60 g. of silica gel using mixtures ofetherpetroleum ether in the range of 30-60% ether (v./v.) as the eluentto give the corresponding a-[1-(oxazole-4-carbonyl)-2-methyl-5-methoxy-3indolyl]-a-trifiuoromethyl acetaldoxime.

EXAMPLE 8 Preparation of a-[1-(0xaz0Ze-4 carbonyl) 2 methyl-5- methoxy 3indolyl]-a-trifluor0methyl acetaldoxime ethyl carbonate To a solution of150 mg. of a-[l-(oxazole-4-carbonyl)- Z-methyl5-methoxy-3-indolyl]-a-trifluoromethyl acetaldoxime in 3 ml. of pyridineis added about 0.2 g. of ethylchloroformate at 0 C. with stirring. Themixture is then stirred at room temperature for 2 hours, poured intowater and extracted with ether. The ethereal solution is washed withwater, dilute HCl and aqueous sodium bicarbonate and then dried oversodium sulfate. Evaporation of the solvent gives mg. of thecorresponding acetaldoxime ethyl carbonate.

EXAMPLE 9 Preparation of a-[1-(oxaz0le-4-carbonyl)-2-methyl-5-methoxy-3-ind0lyl] -a-trifluor0methyl acetonitrile 295 milligrams ofa-[1-(oxazole-4-carbonyl)-2-methyl- 5-methoxy-3-indolyl]-a-trifluoromethyl acetaldoxime ethyl carbonate are heated at 1mm. Hg inan oil bath at C. for 10 minutes. After cooling, the hard yellow film isdissolved in 20% (v./v.) ether in petroleum ether and the solutionpassed through an alumina (6 g.) column and eluted with 600 ml. of thesame solvent to yield the corresponding a [1 (oxazole 4 carbonyl) 2methyl-5-methoxy-3-indolyl]-a-trifluoromethyl acetonitrile.

EXAMPLE 10 A. Preparation of methyloutrifluoromethyl-a-[l-(oxaz0le-4-carbonyl)-2-methyl 5methoxy-3-indolyl] -acetate.A solution of 0.01 mole ofa-[1-(oxazole-4-carbonyl)-2-rnethyl-5-methoxy 3indolylLa-trifluoromethyl acetonitrile and 0.01 mole of methanol in 50ml. dry ether is treated with anhydrous hydrogen chloride at 0-5 C.until the resulting imino methyl ester hydrochloride precipitates. Theprecipitate is collected, Washed with ether and then treated with waterto undergo hydrolysis and yield the corresponding methyla-trifluoromethyl-a-[l- (oxazole-4-carbonyl)-2-methyl 5methoxy-3-indolyl]- acetate.

B. In accordance with the above procedures, but substituting ethanol,isopropanol and tertiary butanol, respectively, for the methanol usedtherein, there are obtained the corresponding ethyl, isopropyl andtertiary butyl esters, respectively.

EXAMPLE 11 Preparation of u-trifluoromethy l-a- 1(oxazole-4-carbonyl)-2-methyl-5-methoxy-3-indolyl] acetic acid Asolution of 3 g. of methyl a-trifiuoromethyl-zx-[ l-(oxazole 4 carbonyl)2 methyl 5 methoxy 3 indolyl]-acetate in 80 ml. of dioxane and 20 ml. of2.5 N hydrochloric acid is maintained at 50 C. for several hours under anitrogen atmosphere. The reaction mixture is concentrated in vacuo toabout 30 ml., diluted with 200 ml. of water, and extracted with ether.The ethereal solution is Washed with Water, dried over sodium sulfate,filtered, and evaporated to a residue. The residue is chromatographed on200 g. of silica gel using mixtures of ether in petroleum ether (v./v.30%-100%) as eluent to yield a-trifluoromethyl a [1 (oxazole 4 carbonyl)2 methyl 5- methoxy-3-indolyl] acetic acid.

EXAMPLE 12 The procedures of Examples 611 are followed using anequivalent quantity of each of the other 1-acyl-3-haloacetyl-indoles ofExample 5 as the starting material in place of the1-(oxazole-4-carbonyl)-2-methyl-3-trifluoroacetyl- S-methoxyindole ofExample 6, and equivalent quantities of the respective indolylintermediates thereafter, to yield the correcpondinga-halomethyl-a-(l-acyl 3 indolyl)- acetic acid.

EXAMPLE 13 Preparation ofa-trifluoromethyl-a-[1-(0xazole-4-carbonyl)-2-methyl-5-methoxy-3-ind0lyl]aceticacid anhydride To a solution of 0.05 mole of a-trifluoromethyl-a-[l-(oxazole 4 carbonyl) 2 methyl 5 methoxy 3 indolylJacetic acid in 300 ml.of dry tetrahydrofuran is added 0.025 mole of dicyclohexyl carbodiimidewith icecooling and stirring. The mixture is allowed to remain at 13 -5C. for 1 hour and then at room temperature (about 25 C.) for anadditional 4-6 hours. The solution is filtered to remove thedicyclohexylurea formed, and concentrated in vacuo to a residue. Theresulting anhydride is recrystallized from a mixture of benzene andpetroleum ether.

EXAMPLE 14 The procedure of Example 13 is followed using an equilvalentquantity of each of the other a-halomethyl-lacyl-3-indolylacetic acidsprepared in Example 12 in place of thea-trifiuoromethyl-a-[1-(oxazole-4-carbonyl)-2-methyl--methoxy-3-indolyl]acetic acid used therein to obtain thecorresponding a-halomethyl-a-(l-acy1-3-indolyl)acetic acid anhydrides.

EXAMPLE 15 A. Preparation of N,N-dimethyl-a-trifluoromethyl-a- [I(oxazole 4 carbonyl) 2 methyl 5 methoxy- 3-indolyl] acetamide.A solutionof 0.01 mole of a-trifluoromethyl a [1 (oxazole 4 carbonyl) 2 methyl-5-methoxy-3-indolyl]acetic acid anhydride in 50 ml. tetrahydrofuran istreated with 0.02 mole of anhydrous dimethylamine at 0 C. with stirring.After one-half hour, the solution is filtered to remove thedimethylamine salt and concentrated in vacuo to yieldN,N-dimethyl-a-trifiuoromethyl a [1 (oxazole 4 carbonyl) 2methyl-5-methoxy-3-indolyl]acetamide which is recrystallized from amixture of benzene and petroleum ether.

B. In accordance with the above procedure, but substituting anequivalent quantity of isopropylamine, diethanolamine, aniline,monomethylaniline, benzylamine, para-chloroaniline, ,B-methoxyethylamine, morpholine and para-methoxy aniline, respectively, in place ofthe dimethylamine used therein, there are obtained, respectively, thecorresponding N-substituted acetamides.

C. The procedure of paragraph 15(A) is followed using dry ammonia gasinstead of dimethylamine. The ammonia is bubbled through thetetrahydrofuran solution of the indolyl acid anhydride. The product isa-trifluoromethyl-a-[1-(oxazole-4-carbonyl)-2-methyl-5-methoxy-3-indolylJacetamide.

D. The procedure of paragraph 15( C) is followed using equivalentquantities of the other indolyl acid anhydrides prepared in Example 14to yield the corresponding indolyl acetamides.

EXAMPLE 16 A. Preparation of isopropyl a trifluoromethyl-a-[I-(oxazole-4-carbonyl)-2-methyl 5-methoxy-3-indo'lyl] acetate.-A solutionof 0.01 mole of a-trifluoromethyl-u- [l-(oxazole-4-carbonyl)-2-methyl 5methoxy-3-indolyl] acetic acid anhydride, 0.01 mole of triethylamine and0.01 mole of isopropanol in 50 ml. of dimethoxyethane is allowed tostand at 0 C. for 1 hour and then at room temperature for 4-6 hours. Thesolution is concentrated in vacuo to about ml. and diluted with 50 ml.of ether. The ether solution is filtered from the triethylamine salt andthen evaporated to give the isopropyl ester.

B. In accordance with the above procedure, but substituting anequivalent quantity of methanol, ethanol, tertiarybutanol, benzylalcohol and ,B-phenylethyl alcohol, respectively, in place of theisopropanol used therein, there are obtained, respectively, thecorresponding esters.

EXAMPLE 17 The procedures of Examples and 16 are followed, respectively,using an equivalent quantity of each of the othera-halomethyl-a-(1-acyl-3-indolyl)acetic acid anhydrides prepared inExample 14 in place of the oc-tfifiLlOIO- methyl a-[l(oxazole-4-carbonyl)-2-methyl-5-methoxy-3- indolyl]acetic acid anhydrideused therein to obtain, respectively, the corresponding N-substitutedacetamides and the corresponding esters.

14 EXAMPLE 1s A. Preparation of the morpholine salt ofot-trifluoromethyl-u-[l-(oxazole 4 carbonyl) -2-methyl-5-meth0xy-3-ind0lyl1acetic acid.To a solution of 0.01 mole of oztrifiuoromethyl a[1-(oxazole-4-carbonyl)-2-methyl-5- rnethoxy-3-indolyl]acetic acid inml. of ether at 0 C. is added a solution of 0.01 mole of morpholine in50 ml. of ether, dropwise, with stirring. The mixture is filtered andthe resulting crystalline morpholine salt of a-trifluoromethyl-a-[1-(oxazole 4 carbonyl)-2-methyl-5-methoxy- 3-indolyl1acetic acid is washedwith ether and dried in vacuo.

B. The procedure of paragraph 18(A) above is followed using, in place ofthe indolyl acid used above, an equivalent quantity of each of theindolyl acids prepared in Examples 11 and 12, to produce the morpholinesalt of each of said acids.

C. The procedure of paragraph 18(A) above is followed using, in place ofmorpholine, and equivalent amount of each of the following amines, toyield the corresponding amine salts of a-trifiuoromethyl-a-[l- (oxazole4 carbonyl) 2 methyl-5-methoxy-3-indolyl] acetic acid: trimethylamine,triethylarnine, n-butylamine, aniline, choline, 2,3-xylidine andpiperazine.

EXAMPLE 19 A. Preparation of sodium a-trifluoromethyl a [1-(0xaz0le-4-carb0nyl)-2-methyl 5 meth0xy-3-z'ndolyl1acetare-To a solutionof 0.01 mole of a-trifluoromethyl-a- [l-(oxazole 4carbonyl)-2-methyl-5-methoxy-3-indolyl] acetic acid in 100 ml. ofmethanol at 0 C. is added a solution of 0.01 mole of sodium methoxide in30 ml. of methanol with stirring. The mixture is concentrated in vacuoat 10-25" C. to about 30 ml. and diluted with 200 m1. ether. Theprecipitated sodium salt is collected on a filter, washed with ether anddried in vacuo.

B. The procedure of paragraph 19(A) is followed using an equivalentquantity of each of the indolyl acids prepared in Example 12, to obtainthe corresponding sodium salt of each of said acids.

C. The procedure of paragraph 19(A) is followed using 0.01 mole of eachof the following alkoxides or hydroxides in place of sodium methoxide,to produce the corresponding metal salts: potassium methoxide, aluminumisopropoxide, magnesium hydroxide and calcium hydroxide.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

We claim:

1. A compound of the formula:

R5 oHooR R is selected from the group consisting of hydroxy, loweralkoxy, benzyloxy, amino, lower alkylamino, di-lower alkylamino, loweralkanolamino, phenylamino, tolylamino, benzylamino, phenylethylamino,lower alkoxy-lower alkylamino and OM, where M is selected from the groupconsisting of ammonium, lower alkylamrnonium, morpholinium, cholinium,glucosammonium, methyl cyclohexylammoni-um, triethyla mmonium,N-butylammonium, anilinium, 2,3- Xylidinium, piperizinium, alkali metalcations, alkali earth cations, magnesium, aluminum, zinc and iron;

R is selected from the group consisting of hydrogen, lower alkyl, loweralkoxy, CF CHF nitro, cyano, aminomethyl, amino, hydroXy,benzylmercapto, lower alkylthio, diphenylamino, benzylamino,p-phenylethylamino, chloro lower alkylamino, chloro phenylamino, chlorobenzylamino, lower alkoXy-lower alkylamino, anisidino, loweralkylanilino and lower alkoxyanilino.

2. A compound of claim 1 wherein R is haloxazole, R is lower alkyl, R istrihalomethyl, R is hydroxy and R is lower :alkoxy.

3. A compound of claim 1 wherein R is lower alkylthiooxazole, R is loweralkyl, R is trihalomethyl, R is hydroxy and R is lower alkoxy.

4. A compound of claim 1 wherein R is oxazole, R is lower alkyl, R istrihalomethyl, R is lower alkoxy and R is lower alkoxy.

5. A compound of claim 1 wherein R is oxaz-ole, R is lower alkyl, Rtrihalomethyl, R is amino and R is lower alkoxy.

6. A compound of claim 1 wherein R is oxazole, R is lower alkyl, R istrihalomethyl, R is diloweralkylamino, and R is lower alkoxy.

7. u Trifiuoromethyl a [l (oXaZole-4-carbonyl)-2-methyl-5-methoXy-3-indolyl] acetic acid.

8. Methyl a trifluorornethyl a-[l-(oxazole-4-carbonyl -2-methyl-5-methoxy-3-indolyl] acetate.

9. Isopropyl a trifluoro-methyl-a-[1-(oXazole-4-carbonyl) -2-met-hyl-5-methoxy-3-indolyl] acetate.

10. or Trifluoromethyl a-[1-(oXazole-4-carbonyl)- Z-methyl-S-methoXy-3-indolyl] acetamide.

11. N,N dimethylu-t-rifluoromethyl-a-(l-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)acetamide.

16 12. A compound of the formula:

CXYZ

| s C=O in which R is selected from the group consisting of oxazole,isoxazole, oxadiazole, and substituted oxazole, isoxazole and oxadiazolein which the substituents are selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, phenyl, benzyl, trifiuoromethyl,cyano, thiocarbamyl, hydroxyloweralkyl, hydroxyphenyl and lower alkylphenyl;

R is selected form the group consisting of hydrogen,

lower alkyl, lower alkenyl, phenyl, tolyl and benzyl;

R is selected from the group consisting of hydrogen,

lower alkyl, lower alkoxy, CF OHF nitro, cyano, aminomethyl, amino,hydroxy, henzylmercapto, lower alkylthio, diphenylamino, benzylamino,fl-phenylethylamino, chloro lower alkylamino, chloro phenylamino, chlorobenzylamino, lower alkoxy-lower alkylamino, anisidino, loweralkylanilino and lower alkoxyanilino, and

XYZ are selected from the group consisting of hydrogen and halogen, nomore than two being hydrogen at any one time.

13. A compound of claim 12 wherein R is oxazolyl, R is lower alkyl, X,Y, and Z are each halo and R is lower alkoxy.

14. 1 p (oxazole-4-carbonyl)-2-methyl-3-trifiuoroacetyl-S-methoxyindole.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

RICHARD J. GALLAGHER, Assistant Examiner.

1. A COMPOUND OF THE FORMULA: